LLP2A-bisphosphonate conjugates for osteoporosis treatment

Abstract

The present invention provides compounds and pharmaceutical compositions of a peptidomimetic ligand, e.g. LLP2A, conjugated with a bisphosphonate drug, e.g. Alendronate. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of osteoporosis and for the promotion of bone growth due to their specificity for the α 4 β 1 integrin on mesenchymal stem cells and for the surface of bone.

What is claimed is: 
     
       1. A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein each R 1  and R 2  is independently selected from the group consisting of halogen,
 C 1-6  alkyl, C 1-6  alkoxy, and C 1-6  haloalkyl; 
 R 3  is selected from the group consisting of H, C 1-6  alkyl and C 3-8  cycloalkyl; 
 X is selected from the group consisting of O, S and NH; 
 Y is selected from the group consisting of O and NH; 
 Z is a peptide having 3-20 independently selected amino acids, wherein at least one amino acid is selected from the group consisting of an unnatural amino acid and a D-amino acid; 
 L is a linker 
 D is a hisphosphonate drug; 
 subscripts m, n and q are each independently from 0 to 2; 
 and salts and isomers thereof. 
 
     
     
       2. The compound of  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound of  claim 1 , wherein peptide Z has the formula:
   -X AA1 -X AA2 -X AA3 -(X AA4 ) p - 
 
       wherein
 X AA1  is selected from the group consisting of a hydrophobic amino acid and derivatives of lysine, homolysine (Hly), ornithine (Orn) and α,γ-diaminobutyric acid (Dbu); 
 X AA2  is a negatively charged amino acid; 
 X AA3  is a hydrophobic amino acid; 
 X AA4  is selected from the group consisting of a naturally-occurring amino acid, an unnatural amino acid, and a D-amino acid; and 
 subscript p is 0 or 1. 
 
     
     
       5. The compound of  claim 4 , wherein
 X AA1  is lysine-A38 (Lys38); 
 X AA2  is α-aminohexanedioic acid (Aad); 
 X AA  is a D-amino acid; and 
 subscript p is 0. 
 
     
     
       6. The compound of  claim 1 , wherein peptide Z is selected from the group consisting of -Lys38-Aad-D-Phe, -Lys38-Aad-Ach, -Lys38-Aad-D-Nal-2, -Lys38-Aad-Ile, -Lys38-Aad-Val, and -Lys38-Aad-Leu. 
     
     
       7. The compound of  claim 1 , wherein peptide Z is -Lys38-Aad-Ach. 
     
     
       8. The compound of  claim 1 , wherein tinker L comprises at least one of N-(8-amino-3,6-dioxa-octyl)succinamic acid (EBES) and polyethylene glycol (PEG). 
     
     
       9. The compound of  claim 1 , wherein linker L is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein k is from 0 to 6. 
       
     
     
       10. The compound of  claim 1 , wherein D has the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 4  is selected from the group consisting of H, OH and halogen; 
 R 5  is selected from the group consisting of H and C 1-6  alkyl; and 
 subscript t is from 1 to 6. 
 
     
     
       11. The compound of  claim 1 , wherein D has the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 1 , having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       13. A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
       14. A method of treating osteoporosis, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1 . 
     
     
       15. A method of promoting bone growth, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1 . 
     
     
       16. A method of treating low bone mass, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1 . 
     
     
       17. A method of treating secondary induced low bone mass in a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 , wherein the disease or condition is arthritis, immunosuppressant induced low bone mass, or chemotherapy induced low bone mass. 
     
     
       18. A method of treating a bone injury, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
       19. The method of  claim 18 , wherein the bone injury is a fracture. 
     
     
       20. A method of treating secondary induced low bone mass in a disease selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, celiac disease, inflammatory bowel disease, and ulcerative colitis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
       21. A method of treating steroid induced osteoporosis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
       22. The method of any of  claims 14 - 16 ,  17 ,  18 - 19 , or  21 , further comprising administering to the subject mesenchymal stem cells with the compound of  claim 1 .